Polycythemia, or an inappropriate increase in red blood cell mass, may be either congenital or acquired. Primary polycythemia, also known as polycythemia vera (PV), is an acquired disease that derives from the clonal expansion of myeloid progenitor cells that have acquired the JAK2-V617F mutation. This mutation, observed in 95% of PV cases, induces excessive maturation of erythrocyte progenitors resulting in excess circulating mature erythrocytes. Approximately 2 per 100,000 people have PV, with the prevalence being higher in men than women. Significant morbidity and mortality due directly to increased red cell mass is observed including cerebrovascular events, myocardial infarction, deep venous thrombosis, and pulmonary embolism. Median survival from the time of diagnosis is approximately 13 years, with more than 40% of deaths attributed to thrombotic events. Currently, the primary therapy for this disease is control of red cell mass by phlebotomy. For the appropriate treatment of PV, therapeutic compounds must be developed to directly lower red cell mass without significant toxicity.
Anemia, which is a decrease in the normal number of red blood cells or a decrease in the normal level of hemoglobin in the blood, is the most common disorder of the blood and can be caused by various factors, including excessive blood loss (e.g., hemorrhage), excessive destruction of blood cells (e.g., hemolysis), and deficient red blood cell production (e.g., defective erythropoiesis). Current treatments for anemia are often dependent on the underlying cause and include iron supplementation, exogenous erythropoietin, and blood transfusions. In particular, aplastic anemia results from the inability of the bone marrow to produce a sufficient amount of blood cells. Aplastic anemia typically does not respond to conventional anti-anemia treatments and can require bone marrow transplants to ameliorate the condition. Thus, there is a continuing need for additional treatments, particularly those that act to increase blood cell production, for anemia.
MiRNAs have recently been implicated in a number of biological processes including regulation of developmental timing, apoptosis, fat metabolism, and hematopoietic cell differentiation among others. MiRNAs are small, non-protein coding RNAs of about 18 to about 25 nucleotides in length that are derived from individual miRNA genes, from introns of protein coding genes, or from poly-cistronic transcripts that often encode multiple, closely related miRNAs. See review by Carrington et al. (Science, Vol. 301(5631):336-338, 2003). MiRNAs act as repressors of target mRNAs by promoting their degradation, when their sequences are perfectly complementary, or by inhibiting translation, when their sequences contain mismatches. Many miRNAs are tissue specific, allowing them to regulate ubiquitously expressed genes in a tissue specific manner. Due to these properties, it is likely that the regulation of miRNAs could therapeutically impact complex disease states in a tissue specific manner.